Nonsyndromic hearing impairment (NSHI) is the most heterogeneous trait known with ~170 mapped loci and 98 genes identified. It is hypothesized that many NSHI genes remain to be discovered due to the many different processes that can malfunction within the inner ear and cause hearing impairment. To date, most NSHI gene identification studies have been performed in families ascertained in Europe and Asia with the greatest number of findings in NSHI families from the Middle East and the Indian Subcontinent. In order to get a complete picture of the genes and variants involved in NSHI, gene identification needs to be performed in additional populations, in particular sub-Saharan Africans. Despite many identified NSHI genes, only GJB2 and GJB6 have been systematically studied in sub-Saharan Africans. Other studies in sub-Saharan Africans have only reported novel variants in known NSHI genes. Additionally NSHI is understudied in African-Americans and little is known about the genetic etiology of NSHI in this population. Therefore little is known about the allelic architecture and frequency of NSHI-causal variants in sub-Saharan Africans and African-Americans. Our preliminary studies of 10 NSHI families from Cameroon using the OtoSCOPE sequencing array demonstrated that ~30% of NSHI genes in Cameroon are either not present in other populations or have yet to be identified. However this estimate of 30% may be low due to the limited region of study subject ascertainment. A recent study of 51 hearing impaired African-Americans using OtoSCOPE demonstrated that 74% of the study subjects did not have a variant in a known NSHI gene. We estimate that known pathogenic variants in NSHI genes only explain ~4.1% of ARNSHI in African-Americans, which is the most common form of NSHI. To identify novel NSHI genes that are important to individuals of African ancestry, we will collect 125 families that segregate early-onset (<6 years of age) autosomal recessive NSHI, 500 early-onset NSHI probands and 500 controls from South Africa (Xhosa ancestry) and Cameroon. This will be the largest study of NSHI to date in sub-Saharan Africans. Exome and whole genome sequencing, filtering approaches and bioinformatic evaluation will be used to find genes containing pathogenic NSHI variants. These genes will be followed-up with functional and expression studies. The identification of novel NSHI genes in the sub-Saharan African population will give us a better insight into the genetic etiology of hearing impairment. Improved knowledge of genes and proteins that are essential to the auditory process will aid in the development of therapeutic interventions and genetic screening protocols for early diagnosis of NSHI. This study has high public health significance, in particular for minority populations, since it will improve genetic screening and in the future prediction of cochlear implant and treatment outcomes in sub-Saharan Africans, African-Americans and Hispanic-Americans of African descent.